Glial role in oxaliplatin-induced neuropathic pain

• Published in: Experimental neurology 2014-11, Vol.261, p.22-33
• Main Authors: Di Cesare Mannelli, Lorenzo, Pacini, Alessandra, Micheli, Laura, Tani, Alessia, Zanardelli, Matteo, Ghelardini, Carla
• Format: Article
• Language: English
• Subjects: Animals; Antineoplastic Agents - toxicity; Astrocyte; Body Weight - drug effects; Calcium-Binding Proteins - metabolism; Cell Count; Chemotherapy induced neuropathic pain; Disease Models, Animal; Fluorocitrate; Ganglia, Spinal - pathology; Hyperalgesia - physiopathology; Male; Microfilament Proteins - metabolism; Microglia; Minocycline; Minocycline - pharmacology; Motor Activity - physiology; Neuralgia - chemically induced; Neuralgia - pathology; Neuralgia - physiopathology; Neuroglia - drug effects; Neuroglia - physiology; Neurons - drug effects; Neuroprotection; Organoplatinum Compounds - toxicity; Pain Measurement; Rats; Rats, Sprague-Dawley; Reaction Time - drug effects; Time Factors
• ISSN: 0014-4886; 1090-2430
• DOI: 10.1016/j.expneurol.2014.06.016

Oxaliplatin, a platinum-based chemotherapeutic agent, has become a standard treatment for advanced colorectal cancer. The dose-limiting toxicity of this compound is the development of peripheral neuropathy. A tangled panel of symptoms, sensory loss, paresthesia, dysesthesia and pain, may be disabling for patients and adversely affect their quality of life. Recently, we described a characteristic glial activation profile in a rat model of oxaliplatin-induced neuropathy. Glial cells are considered a new pharmacological target for neuropathic pain relief but its relevance in chemotherapy-dependent neuropathies is debated. Aimed to evaluate the significance of glial activation in pain generated by oxaliplatin, the microglial inhibitor minocycline or the astrocyte inhibitor fluorocitrate were continuously infused by intrathecal route in oxaliplatin-treated rats. Both compounds significantly reduced oxaliplatin-evoked pain though the efficacy of fluorocitrate was higher revealing a prominent role of astrocytes. Immunohistochemical analysis of the dorsal horn confirmed the specific Iba1-positive cell inhibition caused by minocycline as well as the selectivity of fluorocitrate on GFAP-positive cells. The activation of astrocytes in minocycline-treated rats suggests a microglia-independent modulation of astrocytes by oxaliplatin neurotoxicity. Neither the selective activation of astrocyte after minocycline treatment nor the exclusive microglial response after fluorocitrate is able to evoke pain. Morphometric and morphological determinations performed on dorsal root ganglia evidenced that the glial inhibitors did not prevent the oxaliplatin-dependent increase of eccentric nucleoli and multinucleolated neurons. The decrease of soma area was also unaltered. In summary, these data highlight the role of central glial cells in oxaliplatin-dependent neuropathic pain. On the other hand, glial inhibition is not associated with neuroprotective effects suggesting the need for careful modulation of glial signaling to prevent the pathophysiology that leads to persistent neuropathic pain. •Prevention of microglia or astrocyte activation reduces oxaliplatin-dependent pain.•Astrocytes have a preponderant role.•Astrocyte number increase is not consequential to microglial activation.•Oxaliplatin induces pain by the synergistic signal of microglia and astrocytes.•Glial cell inhibition is not associated with neuroprotection.